Familial amyotrophic lateral sclerosis (FALS) and 'pure' familial spastic paraparesis (FSP) are prototypic disorders of motor neuron degeneration that affect both the upper and lower motor neurons (FALS) or primarily the upper motor neuron (FSP). These phenotypes of motor neuron degeneration are genetically heterogeneous. The long term goal of my laboratory is to identify the genetic contribution to the pathogenesis of these disorders in order to formulate interventions based on disease mechanism to prevent, postpone and treat these disorders. In this proposal we propose to (1) map the gene(s) for (i) FALS in large dominant FALS families that do not have mutations in the gene for SOD1 (Cu, Zn superoxide dismutase) and (ii) in large dominant 'pure' FSP families that do not have mutations in the gene for SOD1 (Cu, Zn superoxide dismutase) and (ii) in large dominant 'pure' FSP families that do not map to 2p, 14q or 15q (2) further refine the physical map around the 2p locus of dominant 'pure' FSP and the 2q33 and the newly discovered, 15q loci of autosomal recessive familial ALS, and (3) clone the genes responsible for the disorders at those loci. We will use our newly acquired automated genotyping setup to rapidly screen banked DNA from FALS and FSP families and assign gene loci using genetic linkage techniques. Simultaneously, we will test known genes and full length cDNA sequences of Expressed Sequence Tags (ESTs) that physically map to the loci for dominant FSP on 2p and/or cosmids mapped to YAC contigs on these regions. Once the non-SOD1 dominant FALS loci or additional FSP loci are identified, we will proceed to develop refined maps of loci, and utilize physical mapping and cloning techniques similar to those described above. Thus, such am assembly of genes that cause motor neuron degeneration will provide a crucial resource to search for points at which pathways leading from these genes converge in the pathogenesis of neuronal degeneration.